This application is designed to facilitate the training and career development of the applicant, whose goal is to be an independent investigator. The proposed studies provide the applicant with a wide range of cell biology and biochemistry techniques to allow the applicant to develop expertise in diabetes research. The career development plan includes a compelling research project with potential clinical applications, laboratory technique training, and didactic scientific seminars. Type 2 diabetes is characterized by impaired insulin action in tissues such as muscle, liver, and adipose tissue. The long term objective is to determine the mechanisms involved in the pathogenesis of insulin resistance and diabetes. Retinol binding protein 4 (RBP4) is elevated in rodents and humans with obesity and insulin resistance. Injection of purified RBP4 in rodents causes insulin resistance, glucose intolerance, and impaired insulin signaling in skeletal muscle. STRA6 (Stimulated by retinoic acid) was recently identified as a high affinity receptor for RBP4. This grant will test the hypothesis that RBP4 causes insulin resistance in part through its interactions with STRA6 in tissues such as adipose tissue and skeletal muscle utilizing cell culture studies, primary tissue explants, and in vivo models. In specific aim #1, the importance of RBP4-STRA6 interactions in glucose metabolism and insulin signaling will be determined in cultured myocytes, and the applicant will investigate the mechanisms by which the RBP4-STRA6 pathway alters glucose homeostasis. Aim #2 will determine if STRA6 mediates RBP4-induced insulin resistance in skeletal muscle. This will be accomplished by determining glucose homeostasis in the skeletal muscle specific STRA6 knockout mouse and by measuring glucose uptake and insulin signaling in isolated muscle. Aim #3 will determine if RBP4-STRA6 interactions in adipose tissue alter whole body glucose homeostasis and the development of obesity. Glucose metabolism, insulin sensitivity, body composition, and energy expenditure will be studied in mice treated with STRA6 antisense oligonucleotides and in the adipose tissue STRA6 knockout mouse. Since STRA6 mediates the cellular uptake of retinol, serum and tissue levels of retinoids such as retinol and retinoic acid will be determined. PUBLIC HEALTH RELEVANCE: The proposed experiments will lead to a better understanding of mechanisms involved in the pathogenesis of insulin resistance and type 2 diabetes. New therapeutic targets to treat insulin resistance could be designed to target the retinoid-RBP4-STRA6 pathway.